Pathophysiology

Breast cancer is a heterogeneous disease capable of being categorised into a number of histological subtypes. However, breast cancer is also frequently characterised as four main subtypes (Table 1) based on their gene expression profiles and molecular classification (Makki, 2015). Given the heterogeneity in the condition and the different molecular drivers, treatment needs to be tailored to the individual and the characteristics of their condition.

Table 1. Classification of breast cancer based on receptor expression profile. (Global Status of Advanced/Metastatic Breast Cancer 2005–2015 Decade Report, 2016; Tungsukruthai et al., 2018.

Classification of breast cancer based on receptor expression profile. (Global Status of Advanced/Metastatic Breast Cancer 2005; 2015 Decade Report, 2016; Tungsukruthai et al., 2018).


The importance of assessing hormone receptor (HR) and HER2 expression profiles is highlighted by the fact that they can be both prognostic and predictive of therapy response (Santa-Maria, 2015). The most common breast cancer subtype is HR+, representing the majority of breast cancers. However, the HER2 expression profile should also be considered (Figure 2) (Howlader et al., 2014).

Prevalence of breast cancer subtypes among 57,483 patients enrolled in the US Surveillance, Epidemiology, and End Results (SEER) registries TN, triple negative.

Figure 2: Prevalence of breast cancer subtypes among 57,483 patients enrolled in the US Surveillance, Epidemiology, and End Results (SEER) registries TN, triple negative (Howlader et al., 2014).

Hormone receptor and breast cancer progression

The majority of breast cancers are hormone receptor positive meaning ≥1% of tumour cells have positive nuclear staining for oestrogen receptor (ER) and/or progesterone receptor (PR) via immunohistochemistry (IHC). A cut-off of 1% is used as patients with even these low levels may benefit from hormonal therapy (Shah et al., 2014). This increase in hormone receptor expression commonly seen in breast cancer cells suggest a switch from paracrine to autocrine signalling by steroid hormones (Anderson, 2002; Brisken, 2002; Rosen, 2003). Interestingly, the expression of oestrogen receptor α (ERα), the predominant form of the receptor in the mammary epithelium, is frequently maintained in metastatic tumours and is still expressed in 65–70% of distant metastases (Saha Roy & Vadlamudi et al., 2012). Signalling via ERα has been shown to promote cell proliferation, survival, migration and epithelial–mesenchymal transition – all key factors in the development of many cancers (Saha Roy & Vadlamudi et al., 2012).

Nuclear and extranuclear actions of ERα signalling in breast cancer. EMT, Epithelial–mesenchymal transition; MMP, matrix metalloproteinases.

Figure 3: Nuclear and extranuclear actions of ERα signalling in breast cancer. EMT, Epithelial–mesenchymal transition; MMP, matrix metalloproteinases (Saha Roy & Vadlamudi et al., 2012).

The signalling pathways activated as a consequence of elevated PR levels are less well defined. Progesterone has been observed to stimulate mammary stem cells and promote cell proliferation resulting in a hypothesis that progesterone signalling plays a role in the progression of early breast cancer. However, its role appears to be context dependent. Where it may play a role in the early stages of breast cancer, in breast carcinoma, it can antagonise oestrogen signalling and its presence is associated with favourable prognosis, less aggressive cancer and better overall survival (Grimm et al., 2016).

HER2 and breast cancer progression

Human epidermal growth factor receptor 2 (HER2) is a proto-oncogene encoding a transmembrane tyrosine kinase growth factor that is a member of the epidermal growth factor receptor (EGFR) family. Approximately, 20% of breast cancers are positive for HER2, with assessment usually by IHC, although fluorescent in situ hybridisation (FISH) can be used when IHC is equivocal (Shah et al., 2014; Elster et al., 2015).

Activation and dimerization of the HER2 receptor with another member of the HER family of receptors results in activation of intracellular signalling pathways promoting cell proliferation, growth, survival and motility (de Melo Gagliato et al., 2016).

HER2 activation and signalling in breast cancer.

Figure 4: HER2 activation and signalling in breast cancer (adapted from de Melo Gagliato et al., 2016).

Progression of triple negative breast cancer

Triple negative breast cancer (TNBC), without the characteristic HR+ and/or HER2 expression of most (80–85%) breast cancers, is a complex and aggressive subtype that causes a disproportionate number of deaths (~25%) (Morris et al., 2007; Rastelli et al., 2010). Triple negative breast cancers are also more likely to metastasise within 5 years of diagnosis compared with non-TNBCs, while the median time to death and overall survival are also worse (Carey et al., 2007; Dent et al., 2007).

Gene expression profiling of TNBC has helped characterise four subtypes (basal-like 1, basal-like 2, luminal androgen receptor and mesenchymal) (Lehmann et al., 2016). However, significant molecular heterogeneity is observed within these subtypes and each of the four subtypes has been observed to co-occur within a single tumour (Table 1) (Gao et al., 2016; Lee & Djamgoz, 2018).

Table 2: Classification and gene expression profiles of TNBC. (Lee & Djamgoz, 2018).

Classification and gene expression profiles of TNBC. (Lee & Djamgoz, 2018).