The response of
breast cancer patients to endocrine
therapy is guided by the expression of two
steroid hormone receptors (HR):
estrogen receptor alpha (
ERalpha) and/or
progesterone receptors (PR). In most laboratories the expression of these predictive markers is studied by immunohistochemistry (IHC) in the
breast cancer biopsy samples. Another molecular marker that is being increasingly examined in
breast cancer is the
oncoprotein Her-2/neu, whose expression/amplification predicts the response to anti-Her-2/neu
immunotherapy. The co-expression of HR with that of Her-2/neu is infrequent (most reports agree on this), however, there are some conflicting reports about the clinical implications in term of response to endocrine
therapy in the patients that co-express HR and Her-2/neu. We have examined these molecular markers for a number of years in our
tumor bank, in this dissertation we will present the method and cut-off to study these markers, the correlations between their expression, and the follow-up of the patients that received
tamoxifen-based endocrine
therapy, alone or following
chemotherapy. We confirmed that the co-expression of HR with Her-2/neu is infrequent, and that these patients presented both a shorter disease free survival and overall survival. Our results will be compared with others related recently published. For example, the
aromatase inhibitor anastrozole appears to be an effective endocrine treatment in HR+ patients, irrespective of the Her-2/neu status. We will present data on the molecular mechanisms that could explain the relatively poor outcome of these patients.
Heregulin has been found to be a potent inducer of heat shock factor 1 (HSF1) activity and of
heat shock protein (Hsp) synthesis in
breast cancer cells and HSF1 activation plays a role in the tumorigenic changes induced by
heregulin,
heregulin exerts its tumorigenic changes through the cell surface
tyrosine kinase receptors c-erbB-3 and c-erbB-4 which are able to form dimers with the "ligandless" Her-2/neu. We found that HSF1 associates with
metastasis associated
protein 1 (MTA1) on the promoters of genes as well as other molecules involved in gene repression (HDAC1, HDAC2) in a manner that is enhanced by either
heregulin exposure or heat shock. ERs, although promoting the growth of
breast cancer cells are less associated with invasion/
metastasis and ER-induced gene expression is involve in this effect.
Heregulin can overcome the protective effects of ER and at least a component of this appears to be due to MTA1 repression of ERE dependent transcription, HSF1 and MTA1 cooperate in gene repression. The co-expression of HSF1 and MTA1 was confirmed by IHC in human
breast cancer biopsy samples.